By Ellin Kavanagh
For nearly 50 years, physicians have been using a type of cellular therapy, called bone marrow transplantation (BMT), that revolutionized treatment of cancer and blood diseases. BMT provides a way for patients to safely receive more aggressive, and often curative, treatment.
Cellular therapy may be poised to once again transform the treatment of cancer and blood diseases. Now scientists are taking a patient’s or donor’s blood cells and genetically engineering them to specifically target cancer cells and be more effective at battling disease.
“Despite the nearly continuous advances that have been made in the treatment of leukemia, this malignancy remains a leading cause of death in childhood,” says Alan Wayne, MD, director of the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles and professor of Pediatrics at the Keck School of Medicine of the University of Southern California (USC). “At CHLA, we can now offer potent immunotherapies to children with the most resistant cancers.”
– Alan Wayne, MD
Michael Pulsipher, MD
Wayne is lead principal investigator on a multisite trial of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed or resistant acute lymphoblastic leukemia (ALL). He led an earlier CAR-T trial at the National Cancer Institute in which 14 of the 20 young patients treated achieved complete remissions. CHLA is one of a small number of sites offering this novel therapy to pediatric patients.
Two other multicenter CAR-T trials at CHLA are being led by Michael Pulsipher, MD, section head of Blood and Marrow Transplantation, including an approach targeted at patients earlier in their disease phase with minimal residual disease. “There are many types of ALL with a poor outcome after BMT—we need to define patients where CAR-T cell therapy can either help or replace BMT,” says Pulsipher.
Ninety percent of children diagnosed with acute lymphoblastic leukemia are cured. However, of those who relapse, only a minority survive long-term. So when Alexis Bonilla was 11 years old and his disease returned for the third time, his doctor immediately referred him to CHLA.
“I told Alexis’ parents that the good news is we have a new therapy, and after being treated with it, your son has a 90 percent chance of remission,” says Pulsipher. “The not-so-good news is that it might initially make him very sick.”
Alexis’ mom, Daysi Bonilla, and his stepdad, Jorge, agreed right away to have their son in the study.
A T-cell is a type of white blood cell that is part of our defense against viruses, bacteria, and to a lesser extent, cancer. CAR-T therapy harnesses the immune system by engineering the T-cells to specifically attack cancer cells. The opposite of a “one size fits all” strategy, this treatment is individually created for each patient using his or her own cells.
Alexis’ blood was collected and sent to the lab so that his T-cells could be genetically engineered to produce a chimeric antigen receptor (CAR) on their surface. The receptor directs the T-cells to a protein, called CD19, present on leukemia cells. When the CAR-T cell connects with the CD19 protein, the leukemia cell is destroyed.
Alexis received several weeks of high-dose chemotherapy to kill as many leukemia cells as possible. Then his modified T-cells were reinfused.
Relapsed leukemia is often resistant to chemotherapy.
CAR-T Cell Therapy uses a patient's own immune cells to specifically target and destroy leukemia.
“Ninety percent of patients develop a fever after the cells are infused,” says Pulsipher. “It’s a side effect that we want to see because it indicates that the CAR-T cells are functioning appropriately.”
He explains that the greater the number of tumor cells a patient has, the greater the immune response. Sometimes, the battle between the supercharged T-cells and the large number of cancer cells becomes extreme, causing the patient’s blood pressure to plummet.
This reaction, known as cytokine release syndrome, or “cytokine storm,” occurred in Alexis. He was moved to the pediatric intensive care unit so that his response could be safely managed. “It was scary,” says Daysi.
When an investigational therapy is first introduced into the clinic, it is tested in people who have disease that is resistant to all other treatments—basically, the sickest patients.
“As we gain experience with CAR-T and trials are open to a wider variety of patients, I anticipate that we will see less-severe side effects in people with earlier-stage disease,” says Pulsipher, who is also a professor of Pediatrics at the Keck School of Medicine of USC. Until then, he and his colleagues are glad to have this truly life-changing therapy to offer their most seriously ill patients.
Alexis made a rapid recovery. Two months after starting treatment at CHLA, he was ready to return home. He always bounces back, Daysi says.
“He wants life,” adds Jorge.
Blood is removed from the patient and T-cells are separated out. The T-cells are sent to the lab, where the number of cells is expanded and a receptor is added to their surface. The modified cells are returned to the patient intravenously. The receptor acts to help the T-cells recognize and kill leukemia cells.
– Neena Kapoor, MD
At CHLA, the reach of cellular therapy extends beyond cancer to diseases like severe combined immunodeficiency disease, sickle cell disease and other life-threatening blood disorders.
Neena Kapoor, MD, director of the Blood and Marrow Transplant Laboratory, is employing genetically engineered T-cells to make hematopoietic transplants like BMT safer for patients who lack a perfectly matched donor.
A child born with severe combined immunodeficiency disease (SCID) lacks the ability to fight off even the most benign infection. The condition is sometimes referred to as “bubble boy disease” because the child needs to live in a pathogen-free environment to survive.
Babies with this condition usually die of infection before their second birthday unless treated with a hematopoietic stem cell transplant that transfers immune cells from a donor. But what happens if a perfectly matched donor cannot be found?
For ethnic minorities and those of mixed heritage, the chance of finding a full or “perfect” match is significantly less than it is for a Caucasian patient. “In a diverse community like Los Angeles, we needed to work toward finding other options for our patients,” says Kapoor, who is also a professor of Clinical Pediatrics at the Keck School of Medicine of USC.
Since a child gets half of his or her genes from each parent, the half-matched transplant is an option for any child who has at least one living parent. Thanks to this technique, many children who lack a perfect donor match now have access to potentially lifesaving treatments.
For ethnic minorities and those of mixed heritage, the chance of finding a full or "perfect" match is significantly less than it is for a caucasian patient.
Parents are always a half match for their children since the mother and father each contribute 50 percent of the child's genes.
She explains that although CHLA has been doing haploidentical, or half-matched, transplants for babies with SCID since 1980, there are now safer techniques for these high-risk transplants. Under Kapoor’s leadership, CHLA is involved in a clinical trial testing ways to reduce the risk for children with malignant and nonmalignant blood disorders.
“The half-matched transplant offers more patients an opportunity to be cured of their disease,” says Kapoor. “To make the procedure safer, we remove the majority of T-cells—cells that are capable of recognizing self from non-self and can cause graft-versus-host disease. But removal of these cells from the graft can delay immune recovery and increase the risk of a potentially lethal infection.”
To address these concerns, patients on the trial receive genetically modified T-cells that have been engineered to include a safety switch, or “suicide gene,” which can be activated if the patient experiences significant signs of graft-versus-host disease. If that happens, a medication can be given that flips the safety switch, causing the reactive T-cells to self-destruct within hours.
This technique allows Kapoor and her colleagues to safely transplant a greater number of immune cells, which provides the patient with immune function much more quickly.
“Typically, patients spend four to six months in a sterile hospital room waiting for their immune system to rebuild,” says Kapoor. “In this study, we can safely send them home just a few weeks after transplant.”
Like every other baby born in the United States, Lawrence Hunt was screened for a variety of lethal conditions that are treatable but not clinically apparent at birth. Although newborn screening is federally recommended, the number of diseases screened for varies by state. Luckily, Lawrence was born in Apple Valley, California.
“California was one of the first states to screen for severe combined immunodeficiency disease,” says Joseph Church, MD, division head of Clinical Immunology and Allergy at CHLA and professor of Pediatrics at the Keck School of Medicine of USC.
“Ninety percent of children identified through newborn screening survive with treatment. For children not screened at birth, however, survival drops significantly.”
When Lawrence’s parents arrived home with their newborn son, they received a call asking them to return to their local hospital to have the screening repeated. After the results were confirmed, the next call came from Church, who oversees notification and treatment referrals of infants born with SCID in Southern California.
A newborn being tested for SCID
Church also heads the Jeffrey Modell Diagnostic and Research Program for Primary Immunodeficiencies at CHLA. Jeffrey Modell was born with primary immunodeficiency disease. After he passed away, his parents, Vicki and Fred Modell, became advocates and established a foundation in memory of their son. The Modells and Church were among those responsible for California being one of the first states to routinely screen for immune disorders. By 2015, 34 states were screening newborns for immune deficiency diseases, with an additional eight states expected to begin this year.
Church asked the Hunts to come to the hospital for follow-up and treatment. At CHLA, Lawrence’s parents learned that their son was born without an immune system, leaving him at high risk of developing a lethal infection. He required a hematopoietic stem cell transplant that would allow him to develop normal immune function.
“Soon, our baby was moved to the bone marrow transplant unit,” recalls Christina Rwengo, Lawrence’s mom. “He was kept in isolation while we waited for a match.”
Unfortunately, no match was found.
Children not screened at birth experience severe recurrent infections and premature death.
Ninety percent of children identified through newborn screening survive with treatment.
Kapoor met with the parents and told them that when a full match isn’t found, centers like the one at CHLA have had success with half-matched transplants. Either biological parent could serve as the donor. Rwengo volunteered.
“Lawrence had never seen my face or his father’s face—just our eyes—because we had to wear a mask whenever we were with him,” she explains. “This was our first child. We wanted him to be able to see us, his mom and dad, and we wanted to bring him home.”
Kapoor informed the parents about the clinical trial at CHLA, and they readily agreed to participate. In the study, Lawrence received the half-matched transplant plus some of his mom’s white blood cells that had been genetically modified. These cells provided immunity until Lawrence’s own immune system developed.
As hoped, because of those additional cells from his mother, Lawrence was able to emerge from isolation and return home months sooner than he would have with standard treatment.
“He’s a typical, happy 1-year-old,” says his mom. “We are so grateful that Lawrence was tested for SCID at birth. Without the treatment he received at CHLA, he could have died from a minor cold. Instead, he’s home.”
Learn more about clinical trials available at the Children’s Center for Cancer and Blood Diseases: CHLA.org/CancerTrials
Human leukocyte antigen (HLA) proteins are present on every cell in our body and are the primary way that the immune system distinguishes its own cells from foreign proteins—like another person’s cells.
A successful stem cell transplant involves matching the patient’s HLA tissue type with that of a donor. The closer the HLA match between donor and recipient, the better the chances of the transplant’s success.
If the match is not close enough, the body will attack the donor cells and reject the stem cell graft. Or the immune cells from the graft can attack the recipient’s body, resulting in a serious, potentially fatal condition called graft-versus-host disease. In a half-matched transplant, the possibility of graft-versus-host disease is increased because of the imperfect HLA match.
Cellular therapy trials offer new options for patients with diseases previously considered untreatable. Investigators at the Children’s Center for Cancer and Blood Diseases are continuing to expand the portfolio of clinical trials available. In fact, CHLA was recently named a Children’s Oncology Group Phase 1 study site.
“It was a great honor being selected to be one of the 21 members in the National Cancer Institute-sponsored Children’s Oncology Group Phase 1 consortium,” says Alan Wayne, MD, “because it acknowledges the breadth and depth of experience with cancer and clinical trials at CHLA. We are proud to be one of the leading centers in the United States that offer breakthrough therapies to our patients.”
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